Aberrant remodelling of the retinal vasculature is a prominent feature of sight-threatening conditions such as diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration and macular telangiectasia. These vascular changes manifest themselves as both new capillary growth from pre-existing retinal vessels (angiogenesis) and the development of vascular malformations of existing vessels (e.g. telangiectasia). This pathogenic vascular remodelling in these diseases is a major contributing factor to loss of vision.
Similar vascular pathology and dysfunction also accompanies tumour growth, where angiogenesis permits the enlargement and growth of solid tumours, and their metastatic spread.
Leucine-rich alpha-2-glycoprotein 1 (Lrg1 gene identifiers: HGNC: 29480; Entrez Gene: 116844; Ensembl: ENSG00000171236; UniProtKB: P02750) was identified in 1977 (Haupt & Baudner, 1977) and its primary structure determined in 1985 (Takahashi et al, 1985). Lrg1 is highly evolutionarily conserved between mice and humans, polyclonal antibodies to human Lrg1 are commercially available and there are reports of concomitant increases in the level of transforming growth factor beta 1 (TGFβ1), TGFβ receptor II (TGFβRII) and Lrg1 in certain diseases (Sun et al, 1995; Li et al, 2007). Other groups have identified Lrg1 as a biomarker of certain diseases (US 2005/0064516; WO 2008/092214) and as a ligand for cytochrome c (US 2007/0184503). Lynch et al. (2012) demonstrate that microRNA-335 (miR-335) targets Lrg1 leading to decreased migration and invasion of neuroblastoma cells by reducing the phosphorylation status of myosin light chain (MLC).
The present inventors have previously shown that Leucine-rich alpha-2-glycoprotein 1 is a drugable target for the modulation of pathogenic vascular remodelling, particularly in the eye and in tumours that exhibit vasculoproliferation. Therefore, the inventors predicted that antagonising Lrg1 may be useful in the treatment of conditions in which pathogenic vascular remodelling or pathogenic angiogenesis occurs, particularly in the eye in conditions such as neovascular AMD, diabetic retinopathy and retinopathy of prematurity (WO 2011/027129). Wang et al (2013), published by the Inventors, also discloses that Lrg1 is involved in vascular remodelling, and that blocking Lrg1 within the TGFβ signalling complex has the potential to divert TGFβ away from pathogenic vascularisation.
The inventors have also previously found that Lrg1 has a direct effect on neoplastic cells as well as immune cell function, and so may be used as a target in the treatment and/or prevention of cancer by directly affecting these cells. The inventors have demonstrated that targeting Lrg1 has a direct effect on neoplastic cells, and so targeting Lrg1 can also be used to treat and/or prevent cancer by this direct effect on cancer cells, specifically by down-regulating the proliferation of neoplastic cells, rather than by an effect on tumour vascularisation. They have also found that Lrg1 modifies immune cell properties that contribute to the pro-oncogenic environment (WO2013132267).
A hallmark of many cancers is a structurally and functionally abnormal vasculature, which reduces tumour perfusion and enhances hypoxia, invasion, and metastasis (Carmeliet and Jain, 2011). Vascular normalisation in tumours is a developing field, in order to improve the delivery of cytotoxic drugs and immunotherapy to the entire tumour, not just its periphery (Carmeliet and Jain, 2011) (Maes et al., 2014). For effective delivery of cytotoxics and immunotherapy properly perfused and matured blood vessels are required. In addition, hypoxia is a driver of metastasis, promoting poor cell junctions and migration of cancer cells into the circulation. Thus increasing the oxygenation of a tumour could act to reduce the probability that the tumour becomes metastatic. Hypoxia also has adverse effects on the host immune system rendering it less susceptible to immune responses. Any tumour with improved vasculature would become more amenable to treatment and reduce hypoxia. Therefore, there is a desire to identify agents that can normalise the vasculature of tumours.
Many diseases are characterised by the presence of hypoxic tissue, including ischemic heart disease, diabetes and several diseases of the eye. There is a drive to increase the oxygenation of tissues affected by these conditions, to normalise the vasculature, in order to achieve a clinical benefit.